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Mechanisms of tumorigenesis and tumor progression Antonio García de Herreros

Molecular mechanisms that regulate pro-metastatic tumoural stroma

Directed by Dr. Josep Baulida

Just as if it were a wound, the connective tissue surrounding a tumour is activated to regenerate the affected epithelia. This is a common reaction of tumours in the epithelium of soft organs, such as the breast, the lungs, or the intestine, which is promoted by signalling molecules from tumour cells. The consequence is that a network rich in fibronectin fibres and collagen forms around the tumour that facilitates tumour cells to invade adjacent tissues and intravasate the circulatory systems (Fig.1). Our research examines the formation of this desmoplastic response and the influence of the tumour micro-environment properties on the formation of metastases.

The work done in the laboratory has allowed us to describe how cancer activated fibroblasts (CAFs) modulate the organization of the stromal compartment and how the new physical parameters facilitate oriented tumour cell invasion. At the molecular level we have described that CAF activation depends on a transcription factor called Snail1. In CAFs Snail1 behaves as an activator, despite having been described as a repressor in earlier works. Some molecular elements activated by TGFβ like subunit ReIA (p65) of nuclear factor-kB (NF-kB) and PARP1, collaborate with Snail1 to increase the transcription of genes coding for extracellular matrix molecules, such as fibronectin. In addition, Snail1 is necessary for the enzymatic activity of RhoA, which controls the reorganisation of the fibroblast cytoskeleton and enables the polymerisation of extracellular fibres. In infiltrating carcinomas of the breast we have described that the expression of this factor in tumour stromal fibroblasts is an indicator of poor prognosis.

The group's current research is focused on increasing our molecular knowledge of CAF regulation. We are characterising key regulatory enzymes whose activity can be inhibited in vivo. We hope to propose pharmacological tools for reducing desmoplasty that can complement the current antimetastatic treatments targeting tumour cell growth. The in vivo anti-metastatic activity of an inhibitor for an enzyme studied in the lab is shown in Fig. 2.

Figure 2. The inhibitor 1 prevents the stroma reaction and decreases metastasis in MMTV-PYMT mice. Primary tumours in MMTV-PYMT mice treated or untreated with the inhibitor 1 were analysed by immuno histochemistry (hematoxylin-eosin stain). The tumour stromal component was reduced in treated mice. Lung metastatic foci were counted. Plot shows that the inhibitor treatment promotes reduction of the metastatic burden.